Abstract
Malaria parasites cannot multiply in host erythrocytes without cholesterol because they lack complete sterol biosynthesis systems. This suggests parasitized red blood cells (pRBCs) need to capture host sterols, but its mechanism remains unknown. Here we identified a novel high-density lipoprotein (HDL)-delivery pathway operating in blood-stage Plasmodium. In parasitized mouse plasma, exosomes positive for scavenger receptor CD36 and platelet-specific CD41 increased. These CDs were detected in pRBCs and internal parasites. A low molecular antagonist for scavenger receptors, BLT-1, blocked HDL uptake to pRBCs and suppressed Plasmodium growth in vitro. Furthermore, platelet-derived exosomes were internalized in pRBCs. Thus, we presume CD36 is delivered to malaria parasites from platelets by exosomes, which enables parasites to steal HDL for cholesterol supply. Cholesterol needs to cross three membranes (RBC, parasitophorous vacuole and parasite’s plasma membranes) to reach parasite, but our findings can explain the first step of sterol uptake by intracellular parasites.
Highlights
Cholesterol is an important lipid for cellular homeostasis and cell membranes and it is required for protein functioning and lipid asymmetry (Rog and Vattulainen, 2014; Steck and Lange, 2018)
The uptake of high-density lipoprotein (HDL) by parasitized erythrocyte is mediated by CD36 and SR-BI that are acquired from platelet-derived exosomes through the interaction with erythrocytes
Translocations of cholesterol from lipoproteins and extracellular space to erythrocytes could occur in the form of cholesteryl ester and free cholesterol (Ohkawa et al, 2020)
Summary
Cholesterol is an important lipid for cellular homeostasis and cell membranes and it is required for protein functioning and lipid asymmetry (Rog and Vattulainen, 2014; Steck and Lange, 2018). Cholesterol in erythrocyte membrane is sorted into the internal malaria parasite (Hayakawa et al, 2020) and a few reports have indicated that Niemann-Pick C1-like 1 (NPC1L1) is involved in cholesterol uptake in apicomplexans (Ehrenman et al, 2013; Istvan et al, 2019). These reports suggest that some protozoans acquire host sterols, raising the prospect that sterol supply to them may be a potential therapeutic target in these pathogens.
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